ABSTRACT Over the past decade of this award, we have made substantial progress toward understanding the adverse impact of chronic kidney disease (CKD) on the health of older adults. Kidney function declines steadily with age, even in the absence of any clinical risk factors, and reduced kidney function is strongly associated with myriad cardiovascular and non-cardiovascular morbidities. In addition to glomerular impairments, we have learned that kidney tubule dysfunction, fibrosis, and injury predict adverse clinical outcomes. These results suggest that kidney tubular health is pivotal for understanding the development and progression of kidney disease. In extrarenal conditions affecting older adults such as heart failure or dementia, mitochondrial dysfunction appears to have a major role in pathogenesis. Like the heart and brain, the kidney tubules rely upon mitochondrial energy metabolism to support fundamental functions of the organ. In this renewal, we hypothesize that reduced mitochondrial health is a major cause of kidney disease in older adults, driven by reduced mitochondrial abundance and oxidative dysfunction that results from accumulated mutations in the mitochondrial DNA (mtDNA). Our new preliminary data implicate unexpectedly striking relationships between circulating mtDNA, intrarenal mitochondrial health, and functional renal outcomes. With emerging therapeutic interest in mitochondria, this proposal could also lead to novel therapies to prevent and treat CKD. We will leverage innovations in mtDNA assessment to measure its quantity by copy number and its quality by newly developed next-gen sequencing methods for mutation burden. Published results already link these measures to overall aging. We will apply these techniques across three translational Aims: the first two Aims will be conducted in large, well- characterized cohorts and the third Aim will use human kidney tissue. The first Aim will evaluate whether mtDNA quantity and quality are associated with risk for acute kidney injury in persons undergoing cardiac surgery. The second Aim will evaluate associations of the same mtDNA measures with development of CKD and with progression to kidney failure. The third Aim will utilize a suite of validated techniques to investigate mitochondrial health in situ using archived kidney tissue from older adults with and without kidney disease: we will compare measures of mitochondrial biogenesis, mitochondrial quantity, oxidative phosphorylation capacity, and ultrastructural appearance, and then evaluate their associations with histopathology and clinical status. These Aims will translate the emerging renal biology of mitochondria into human kidney disease in older adults. Positive results would: 1) advance mtDNA quantity and quality as potential therapeutic targets for kidney diseases; 2) develop innovative methods for the assessment of mitochondria in kidney tissue; and 3) inform selection of patients for future clinical trials of therapies targeted to the mitochondria.